Gene therapy development in hearing research in China

Abstract

Sensorineural hearing loss, the most common form of hearing impairment, is mainly attributable to genetic mutations or acquired factors, such as aging, noise exposure, and ototoxic drugs. In the field of gene therapy, advances in genetic and physiological studies and profound increases in knowledge regarding the underlying mechanisms have yielded great progress in terms of restoring the auditory function in animal models of deafness. Nonetheless, many challenges associated with the translation from basic research to clinical therapies remain to be overcome before a total restoration of auditory function can be expected. In recent years, Chinese research teams have promoted various developmental efforts in this field, including gene sequencing to identify additional potential loci that cause deafness, studies to elucidate the underlying molecular mechanisms, and research to optimize vectors and delivery routes. In this review, we summarize the state of the field and focus mainly on the progress of gene therapy in animal model studies and the optimization of therapeutic strategies in China.

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Fig. 1: Schematic illustration of the cochlear structure and injection routes.

References

  1. 1.

    Sun XB, Wei ZY, Yu LM, Wang Q, Liang W. Prevalence and etiology of people with hearing impairment in China. Zhonghua Liu Xing Bing Xue Za Zhi. 2008;29:643–6.

    PubMed  Google Scholar 

  2. 2.

    Géléoc GS, Holt JR. Sound strategies for hearing restoration. Science. 2014;344:1241062.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Smith RJ, Bale JF Jr., White KR. Sensorineural hearing loss in children. Lancet. 2005;365:879–90.

    PubMed  Google Scholar 

  4. 4.

    Wolber LE, Steves CJ, Spector TD, Williams FM. Hearing ability with age in northern European women: a new web-based approach to genetic studies. PLoS ONE. 2012;7:e35500.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Heinonen-Guzejev M, Vuorinen HS, Mussalo-Rauhamaa H, Heikkilä K, Koskenvuo M, Kaprio J. Genetic component of noise sensitivity. Twin Res Hum Genet. 2005;8:245–9.

    PubMed  Google Scholar 

  6. 6.

    Nelson PB, Jin SH, Carney AE, Nelson DA. Understanding speech in modulated interference: cochlear implant users and normal-hearing listeners. J Acoust Soc Am. 2003;113:961–8.

    PubMed  Google Scholar 

  7. 7.

    Li C, Samulski RJ. Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet. 2020;21:255–72.

    CAS  PubMed  Google Scholar 

  8. 8.

    Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377:1713–22.

    CAS  PubMed  Google Scholar 

  9. 9.

    Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, et al. Long-term effect of gene therapy on Leber’s congenital amaurosis. N Engl J Med. 2015;372:1887–97.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Zhang W, Kim SM, Wang W, Cai C, Feng Y, Kong W, et al. Cochlear gene therapy for sensorineural hearing loss: current status and major remaining hurdles for translational success. Front Mol Neurosci. 2018;11:221.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Dalkara D, Goureau O, Marazova K, Sahel JA. Let there be light: gene and cell therapy for blindness. Hum Gene Ther. 2016;27:134–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Harris JP, Ryan AF. Immunobiology of the inner ear. Am J Otolaryngol. 1984;5:418–25.

    CAS  PubMed  Google Scholar 

  13. 13.

    Praetorius M, Baker K, Brough DE, Plinkert P, Staecker H. Pharmacodynamics of adenovector distribution within the inner ear tissues of the mouse. Hear Res. 2007;227:53–8.

    CAS  PubMed  Google Scholar 

  14. 14.

    Hudspeth AJ. How hearing happens. Neuron. 1997;19:947–50.

    CAS  PubMed  Google Scholar 

  15. 15.

    Barald KF, Kelley MW. From placode to polarization: new tunes in inner ear development. Development. 2004;131:4119–30.

    CAS  PubMed  Google Scholar 

  16. 16.

    Chen P, Segil N. p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti. Development. 1999;126:1581–90.

    CAS  PubMed  Google Scholar 

  17. 17.

    Liu Z, Zuo J. Cell cycle regulation in hair cell development and regeneration in the mouse cochlea. Cell Cycle. 2008;7:2129–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Driver EC, Sillers L, Coate TM, Rose MF, Kelley MW. The Atoh1-lineage gives rise to hair cells and supporting cells within the mammalian cochlea. Dev Biol. 2013;376:86–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Chen P, Johnson JE, Zoghbi HY, Segil N. The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination. Development. 2002;129:2495–505.

    CAS  PubMed  Google Scholar 

  20. 20.

    Zhang Y, Tang Q, Xue R, Gao J, Yang H, Gao Z, et al. Absence of Atoh1 induced partially different cell fates of cochlear and vestibular sensory epithelial cells in mice. Acta Otolaryngol. 2018;138:972–6.

    CAS  PubMed  Google Scholar 

  21. 21.

    Liu Z, Fang J, Dearman J, Zhang L, Zuo J. In vivo generation of immature inner hair cells in neonatal mouse cochleae by ectopic Atoh1 expression. PLoS ONE. 2014;9:e89377.

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Richardson RT, Atkinson PJ. Atoh1 gene therapy in the cochlea for hair cell regeneration. Expert Opin Biol Ther. 2015;15:417–30.

    CAS  PubMed  Google Scholar 

  23. 23.

    Zhong C, Fu Y, Pan W, Yu J, Wang J. Atoh1 and other related key regulators in the development of auditory sensory epithelium in the mammalian inner ear: function and interplay. Dev Biol. 2019;446:133–41.

    CAS  PubMed  Google Scholar 

  24. 24.

    Walters BJ, Coak E, Dearman J, Bailey G, Yamashita T, Kuo B, et al. In vivo interplay between p27(Kip1), GATA3, ATOH1, and POU4F3 converts non-sensory cells to hair cells in adult mice. Cell Rep. 2017;19:307–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Abdolazimi Y, Stojanova Z, Segil N. Selection of cell fate in the organ of Corti involves the integration of Hes/Hey signaling at the Atoh1 promoter. Development. 2016;143:841–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Costa A, Sanchez-Guardado L, Juniat S, Gale JE, Daudet N, Henrique D. Generation of sensory hair cells by genetic programming with a combination of transcription factors. Development. 2015;142:1948–59.

    CAS  PubMed  Google Scholar 

  27. 27.

    Liu W, Xu X, Fan Z, Sun G, Han Y, Zhang D, et al. Wnt signaling activates TP53-induced glycolysis and apoptosis regulator and protects against cisplatin-induced spiral ganglion neuron damage in the mouse cochlea. Antioxid Redox Signal. 2019;30:1389–410.

    PubMed  Google Scholar 

  28. 28.

    Zhu C, Cheng C, Wang Y, Muhammad W, Liu S, Zhu W, et al. Loss of ARHGEF6 causes hair cell stereocilia deficits and hearing loss in mice. Front Mol Neurosci. 2018;11:362.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    He Z, Guo L, Shu Y, Fang Q, Zhou H, Liu Y, et al. Autophagy protects auditory hair cells against neomycin-induced damage. Autophagy. 2017;13:1884–904.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Zhang S, Zhang Y, Dong Y, Guo L, Zhang Z, Shao B, et al. Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea. Cell Mol Life Sci. 2020;77:1401–19.

    CAS  PubMed  Google Scholar 

  31. 31.

    Cheng C, Wang Y, Guo L, Lu X, Zhu W, Muhammad W, et al. Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea. Stem Cell Res Ther. 2019;10:365.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Lu X, Sun S, Qi J, Li W, Liu L, Zhang Y, et al. Bmi1 regulates the proliferation of cochlear supporting cells via the canonical Wnt signaling pathway. Mol Neurobiol. 2017;54:1326–39.

    CAS  PubMed  Google Scholar 

  33. 33.

    Wang T, Chai R, Kim GS, Pham N, Jansson L, Nguyen DH, et al. Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle. Nat Commun. 2015;6:6613.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Cox BC, Chai R, Lenoir A, Liu Z, Zhang L, Nguyen DH, et al. Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. Development. 2014;141:816–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Wang Y, Li J, Yao X, Li W, Du H, Tang M, et al. Loss of CIB2 causes profound hearing loss and abolishes mechanoelectrical transduction in mice. Front Mol Neurosci. 2017;10:401.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Liu L, Chen Y, Qi J, Zhang Y, He Y, Ni W, et al. Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea. Cell Death Dis. 2016;7:e2136.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Hastie E, Samulski RJ. Adeno-associated virus at 50: a golden anniversary of discovery, research, and gene therapy success–a personal perspective. Hum Gene Ther. 2015;26:257–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Wu Z, Asokan A, Samulski RJ. Adeno-associated virus serotypes: vector toolkit for human gene therapy. Mol Ther. 2006;14:316–27.

    CAS  PubMed  Google Scholar 

  39. 39.

    Gu X, Chai R, Guo L, Dong B, Li W, Shu Y, et al. Transduction of adeno-associated virus vectors targeting hair cells and supporting cells in the neonatal mouse cochlea. Front Cell Neurosci. 2019;13:8.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Shu Y, Tao Y, Wang Z, Tang Y, Li H, Dai P, et al. Identification of adeno-associated viral vectors that target neonatal and adult mammalian inner ear cell subtypes. Hum Gene Ther. 2016;27:687–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Shu Y, Tao Y, Li W, Shen J, Wang Z, Chen ZY. Adenovirus vectors target several cell subtypes of mammalian inner ear in vivo. Neural Plast. 2016;2016:9409846.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Landegger LD, Pan B, Askew C, Wassmer SJ, Gluck SD, Galvin A, et al. A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat Biotechnol. 2017;35:280–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Grimm D, Lee JS, Wang L, Desai T, Akache B, Storm TA, et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J Virol. 2008;82:5887–911.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Isgrig K, McDougald DS, Zhu J, Wang HJ, Bennett J, Chien WW. AAV2.7m8 is a powerful viral vector for inner ear gene therapy. Nat Commun. 2019;10:427.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Tan F, Chu C, Qi J, Li W, You D, Li K, et al. AAV-ie enables safe and efficient gene transfer to inner ear cells. Nat Commun. 2019;10:3733.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Akil O. Dual and triple AAV delivery of large therapeutic gene sequences into the inner ear. Hear Res. 2020:107912.

  47. 47.

    Zhang QJ, Han B, Lan L, Zong L, Shi W, Wang HY, et al. High frequency of OTOF mutations in Chinese infants with congenital auditory neuropathy spectrum disorder. Clin Genet. 2016;90:238–46.

    CAS  PubMed  Google Scholar 

  48. 48.

    Wang DY, Wang YC, Weil D, Zhao YL, Rao SQ, Zong L, et al. Screening mutations of OTOF gene in Chinese patients with auditory neuropathy, including a familial case of temperature-sensitive auditory neuropathy. BMC Med Genet. 2010;11:79.

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Akil O, Dyka F, Calvet C, Emptoz A, Lahlou G, Nouaille S, et al. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. Proc Natl Acad Sci USA. 2019;116:4496–501.

    CAS  PubMed  Google Scholar 

  50. 50.

    Chien WW, McDougald DS, Roy S, Fitzgerald TS, Cunningham LL. Cochlear gene transfer mediated by adeno-associated virus: comparison of two surgical approaches. Laryngoscope. 2015;125:2557–64.

    CAS  PubMed  Google Scholar 

  51. 51.

    Suzuki J, Hashimoto K, Xiao R, Vandenberghe LH, Liberman MC. Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction. Sci Rep. 2017;7:45524.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Akil O, Seal RP, Burke K, Wang C, Alemi A, During M, et al. Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron. 2012;75:283–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Kurioka T, Mizutari K, Niwa K, Fukumori T, Inoue M, Hasegawa M, et al. Hyaluronic acid pretreatment for Sendai virus-mediated cochlear gene transfer. Gene Ther. 2016;23:187–95.

    CAS  PubMed  Google Scholar 

  54. 54.

    Akil O, Rouse SL, Chan DK, Lustig LR. Surgical method for virally mediated gene delivery to the mouse inner ear through the round window membrane. J Vis Exp. 2015;97:52187.

    Google Scholar 

  55. 55.

    Wang H, Murphy R, Taaffe D, Yin S, Xia L, Hauswirth WW, et al. Efficient cochlear gene transfection in guinea-pigs with adeno-associated viral vectors by partial digestion of round window membrane. Gene Ther. 2012;19:255–63.

    CAS  PubMed  Google Scholar 

  56. 56.

    Xia L, Yin S, Wang J. Inner ear gene transfection in neonatal mice using adeno-associated viral vector: a comparison of two approaches. PLoS ONE. 2012;7:e43218.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Ji XJ, Chen W, Wang X, Zhang Y, Liu Q, Guo WW, et al. Canalostomy is an ideal surgery route for inner ear gene delivery in big animal model. Acta Otolaryngol. 2019;139:939–47.

    CAS  PubMed  Google Scholar 

  58. 58.

    Hulander M, Wurst W, Carlsson P, Enerback S. The winged helix transcription factor Fkh10 is required for normal development of the inner ear. Nat Genet. 1998;20:374–6.

    CAS  PubMed  Google Scholar 

  59. 59.

    de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, Huber I, Monaco AP, Malcolm S, et al. Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4. Science. 1995;267:685–8.

    PubMed  Google Scholar 

  60. 60.

    Rickheit G, Maier H, Strenzke N, Andreescu CE, De Zeeuw CI, Muenscher A, et al. Endocochlear potential depends on Cl- channels: mechanism underlying deafness in Bartter syndrome IV. EMBO J. 2008;27:2907–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Watanabe A, Takeda K, Ploplis B, Tachibana M. Epistatic relationship between Waardenburg syndrome genes MITF and PAX3. Nat Genet. 1998;18:283–6.

    CAS  PubMed  Google Scholar 

  62. 62.

    Peters LM, Anderson DW, Griffith AJ, Grundfast KM, San Agustin TB, Madeo AC, et al. Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28. Hum Mol Genet. 2002;11:2877–85.

    CAS  PubMed  Google Scholar 

  63. 63.

    Kurima K, Peters LM, Yang Y, Riazuddin S, Ahmed ZM, Naz S, et al. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet. 2002;30:277–84.

    PubMed  Google Scholar 

  64. 64.

    Kubisch C, Schroeder BC, Friedrich T, Lutjohann B, El-Amraoui A, Marlin S, et al. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell. 1999;96:437–46.

    CAS  PubMed  Google Scholar 

  65. 65.

    Grati M, Yan D, Raval MH, Walsh T, Ma Q, Chakchouk I, et al. MYO3A causes human dominant deafness and interacts with protocadherin 15-CD2 isoform. Hum Mutat. 2016;37:481–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Walsh T, Walsh V, Vreugde S, Hertzano R, Shahin H, Haika S, et al. From flies’ eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc Natl Acad Sci USA. 2002;99:7518–23.

    CAS  PubMed  Google Scholar 

  67. 67.

    Ahmed ZM, Morell RJ, Riazuddin S, Gropman A, Shaukat S, Ahmad MM, et al. Mutations of MYO6 are associated with recessive deafness, DFNB37. Am J Hum Genet. 2003;72:1315–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Liu XZ, Walsh J, Mburu P, Kendrick-Jones J, Cope MJ, Steel KP, et al. Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. Nat Genet. 1997;16:188–90.

    CAS  PubMed  Google Scholar 

  69. 69.

    Wang A, Liang Y, Fridell RA, Probst FJ, Wilcox ER, Touchman JW, et al. Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Science. 1998;280:1447–51.

    CAS  PubMed  Google Scholar 

  70. 70.

    Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet. 1997;15:186–9.

    CAS  PubMed  Google Scholar 

  71. 71.

    Tyson J, Tranebjaerg L, Bellman S, Wren C, Taylor JF, Bathen J, et al. IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome. Hum Mol Genet. 1997;6:2179–85.

    CAS  PubMed  Google Scholar 

  72. 72.

    Yang T, Gurrola JG 2nd, Wu H, Chiu SM, Wangemann P, Snyder PM, et al. Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome. Am J Hum Genet. 2009;84:651–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Riazuddin S, Anwar S, Fischer M, Ahmed ZM, Khan SY, Janssen AG, et al. Molecular basis of DFNB73: mutations of BSND can cause nonsyndromic deafness or Bartter syndrome. Am J Hum Genet. 2009;85:273–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Li XC, Everett LA, Lalwani AK, Desmukh D, Friedman TB, Green ED, et al. A mutation in PDS causes non-syndromic recessive deafness. Nat Genet. 1998;18:215–7.

    CAS  PubMed  Google Scholar 

  75. 75.

    Delpire E, Lu J, England R, Dull C, Thorne T. Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nat Genet. 1999;22:192–5.

    CAS  PubMed  Google Scholar 

  76. 76.

    Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature. 1997;387:80–3.

    CAS  PubMed  Google Scholar 

  77. 77.

    Grifa A, Wagner CA, D’Ambrosio L, Melchionda S, Bernardi F, Lopez-Bigas N, et al. Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat Genet. 1999;23:16–8.

    CAS  PubMed  Google Scholar 

  78. 78.

    Wilcox ER, Burton QL, Naz S, Riazuddin S, Smith TN, Ploplis B, et al. Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell. 2001;104:165–72.

    CAS  PubMed  Google Scholar 

  79. 79.

    Zhou XX, Chen S, Xie L, Ji YZ, Wu X, Wang WW, et al. Reduced connexin26 in the mature cochlea increases susceptibility to noise-induced hearing lossin mice. Int J Mol Sci. 2016;17:301.

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Yan D, Zhu Y, Walsh T, Xie D, Yuan H, Sirmaci A, et al. Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise. Proc Natl Acad Sci USA. 2013;110:2228–33.

    CAS  PubMed  Google Scholar 

  81. 81.

    Pawelczyk M, Van Laer L, Fransen E, Rajkowska E, Konings A, Carlsson PI, et al. Analysis of gene polymorphisms associated with K ion circulation in the inner ear of patients susceptible and resistant to noise-induced hearing loss. Ann Hum Genet. 2009;73:411–21.

    CAS  PubMed  Google Scholar 

  82. 82.

    Van Laer L, Carlsson PI, Ottschytsch N, Bondeson ML, Konings A, Vandevelde A, et al. The contribution of genes involved in potassium-recycling in the inner ear to noise-induced hearing loss. Hum Mutat. 2006;27:786–95.

    PubMed  Google Scholar 

  83. 83.

    Vethanayagam RR, Yang W, Dong Y, Hu BH. Toll-like receptor 4 modulates the cochlear immune response to acoustic injury. Cell Death Dis. 2016;7:e2245.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Chen J, Yuan H, Talaska AE, Hill K, Sha SH. Increased sensitivity to noise-induced hearing loss by blockade of endogenous PI3K/Akt signaling. J Assoc Res Otolaryngol. 2015;16:347–56.

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Kurioka T, Matsunobu T, Satoh Y, Niwa K, Endo S, Fujioka M, et al. ERK2 mediates inner hair cell survival and decreases susceptibility to noise-induced hearing loss. Sci Rep. 2015;5:16839.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Jamesdaniel S, Hu B, Kermany MH, Jiang H, Ding D, Coling D, et al. Noise induced changes in the expression of p38/MAPK signaling proteins in the sensory epithelium of the inner ear. J Proteomics. 2011;75:410–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Murai N, Kirkegaard M, Jarlebark L, Risling M, Suneson A, Ulfendahl M. Activation of JNK in the inner ear following impulse noise exposure. J Neurotrauma. 2008;25:72–7.

    PubMed  Google Scholar 

  88. 88.

    Wilson T, Omelchenko I, Foster S, Zhang Y, Shi X, Nuttall AL. JAK2/STAT3 inhibition attenuates noise-induced hearing loss. PLoS ONE. 2014;9:e108276.

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Shen Z, Zheng J, Chen B, Peng G, Zhang T, Gong S, et al. Frequency and spectrum of mitochondrial 12S rRNA variants in 440 Han Chinese hearing impaired pediatric subjects from two otology clinics. J Transl Med. 2011;9:4.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Lang F, Vallon V, Knipper M, Wangemann P. Functional significance of channels and transporters expressed in the inner ear and kidney. Am J Physiol Cell Physiol. 2007;293:C1187–208.

    CAS  PubMed  Google Scholar 

  91. 91.

    Chang Q, Wang J, Li Q, Kim Y, Zhou B, Wang Y, et al. Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange-Nielsen deafness syndrome. EMBO Mol Med. 2015;7:1077–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Gabriel HD, Jung D, Butzler C, Temme A, Traub O, Winterhager E, et al. Transplacental uptake of glucose is decreased in embryonic lethal connexin26-deficient mice. J Cell Biol. 1998;140:1453–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Wang Y, Chang Q, Tang W, Sun Y, Zhou B, Li H, et al. Targeted connexin26 ablation arrests postnatal development of the organ of Corti. Biochem Biophys Res Commun. 2009;385:33–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Yu Q, Wang Y, Chang Q, Wang J, Gong S, Li H, et al. Virally expressed connexin26 restores gap junction function in the cochlea of conditional Gjb2 knockout mice. Gene Ther. 2014;21:71–80.

    CAS  PubMed  Google Scholar 

  95. 95.

    Vreugde S, Erven A, Kros CJ, Marcotti W, Fuchs H, Kurima K, et al. Beethoven, a mouse model for dominant, progressive hearing loss DFNA36. Nat Genet. 2002;30:257–8.

    PubMed  Google Scholar 

  96. 96.

    Shibata SB, Ranum PT, Moteki H, Pan B, Goodwin AT, Goodman SS, et al. RNA interference prevents autosomal-dominant hearing loss. Am J Hum Genet. 2016;98:1101–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Askew C, Rochat C, Pan B, Asai Y, Ahmed H, Child E, et al. Tmc gene therapy restores auditory function in deaf mice. Sci Transl Med. 2015;7:295ra108.

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Gao X, Tao Y, Lamas V, Huang M, Yeh WH, Pan B, et al. Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature. 2018;553:217–21.

    CAS  PubMed  Google Scholar 

  99. 99.

    György B, Nist-Lund C, Pan B, Asai Y, Karavitaki KD, Kleinstiver BP, et al. Allele-specific gene editing prevents deafness in a model of dominant progressive hearing loss. Nat Med. 2019;25:1123–30.

    PubMed  PubMed Central  Google Scholar 

  100. 100.

    Gao X, Xu JC, Wang WQ, Yuan YY, Bai D, Huang SS, et al. A missense mutation in POU4F3 causes midfrequency hearing loss in a Chinese ADNSHL family. Biomed Res Int. 2018;2018:5370802.

    PubMed  PubMed Central  Google Scholar 

  101. 101.

    Cai XZ, Li Y, Xia L, Peng Y, He CF, Jiang L, et al. Exome sequencing identifies POU4F3 as the causative gene for a large Chinese family with non-syndromic hearing loss. J Hum Genet. 2017;62:317–20.

    CAS  PubMed  Google Scholar 

  102. 102.

    He L, Pang X, Chen P, Wu H, Yang T. Mutation in the hair cell specific gene POU4F3 is a common cause for autosomal dominant nonsyndromic hearing loss in Chinese Hans. Neural Plast. 2016;2016:9890827.

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Lin YH, Lin YH, Lu YC, Liu TC, Chen CY, Hsu CJ, et al. A novel missense variant in the nuclear localization signal of POU4F3 causes autosomal dominant non-syndromic hearing loss. Sci Rep. 2017;7:7551.

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Wei Q, Zhu H, Qian X, Chen Z, Yao J, Lu Y, et al. Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss. J Transl Med. 2014;12:311.

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Yang T, Wei X, Chai Y, Li L, Wu H. Genetic etiology study of the non-syndromic deafness in Chinese Hans by targeted next-generation sequencing. Orphanet J Rare Dis. 2013;8:85.

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Zhang C, Wang M, Xiao Y, Zhang F, Zhou Y, Li J, et al. A novel nonsense mutation of POU4F3 gene causes autosomal dominant hearing loss. Neural Plast. 2016;2016:1512831.

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Xu X, Yang Q, Jiao J, He L, Yu S, Wang J, et al. Genetic variation in POU4F3 and GRHL2 associated with noise-induced hearing loss in Chinese population: a case-control study. Int J Environ Res Public Health. 2016;13:561.

    PubMed Central  Google Scholar 

  108. 108.

    Jie H, Tao S, Liu L, Xia L, Charko A, Yu Z, et al. Cochlear protection against cisplatin by viral transfection of X-linked inhibitor of apoptosis protein across round window membrane. Gene Ther. 2015;22:546–52.

    CAS  PubMed  Google Scholar 

  109. 109.

    Liu Y, Okada T, Shimazaki K, Sheykholeslami K, Nomoto T, Muramatsu S, et al. Protection against aminoglycoside-induced ototoxicity by regulated AAV vector-mediated GDNF gene transfer into the cochlea. Mol Ther. 2008;16:474–80.

    PubMed  Google Scholar 

  110. 110.

    Yao XB, Li SL, Zhu HL, Wang XX, Liu H, Yan LY. Protective effect of adeno-associated virus-mediated neurotrophin-3 on the cochlea of guinea pigs with gentamicin-induced hearing loss. Nan Fang Yi Ke Da Xue Xue Bao. 2007;27:1642–5.

    CAS  PubMed  Google Scholar 

  111. 111.

    Liu YH, Ke XM, Qin Y, Gu ZP, Xiao SF. Adeno-associated virus-mediated Bcl-xL prevents aminoglycoside-induced hearing loss in mice. Chin Med J. 2007;120:1236–40.

    CAS  PubMed  Google Scholar 

  112. 112.

    Chen H, Shi L, Liu L, Yin S, Aiken S, Wang J. Noise-induced cochlear synaptopathy and signal processing disorders. Neuroscience. 2019;407:41–52.

    CAS  PubMed  Google Scholar 

  113. 113.

    Liberman MC. Noise-induced and age-related hearing loss: new perspectives and potential therapies. F1000Res. 2017;6:927.

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Moser T, Starr A. Auditory neuropathy—neural and synaptic mechanisms. Nat Rev Neurol. 2016;12:135–49.

    CAS  PubMed  Google Scholar 

  115. 115.

    Chen H, Xing Y, Xia L, Chen Z, Yin S, Wang J. AAV-mediated NT-3 overexpression protects cochleae against noise-induced synaptopathy. Gene Ther. 2018;25:251–9.

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet. 2001;28:92–5.

    CAS  PubMed  Google Scholar 

  117. 117.

    Brownstein Z, Friedman LM, Shahin H, Oron-Karni V, Kol N, Abu Rayyan A, et al. Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families. Genome Biol. 2011;12:R89.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Shearer AE, DeLuca AP, Hildebrand MS, Taylor KR, Gurrola J 2nd, Scherer S, et al. Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing. Proc Natl Acad Sci USA. 2010;107:21104–9.

    CAS  PubMed  Google Scholar 

  119. 119.

    Xia JH, Liu CY, Tang BS, Pan Q, Huang L, Dai HP, et al. Mutations in the gene encoding gap junction protein β-3 associated with autosomal dominant hearing impairment. Nat Genet. 1998;20:370–3.

    CAS  PubMed  Google Scholar 

  120. 120.

    Cheng J, Zhu Y, He S, Lu Y, Chen J, Han B, et al. Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64. Am J Hum Genet. 2011;89:56–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Zhao Y, Zhao F, Zong L, Zhang P, Guan L, Zhang J, et al. Exome sequencing and linkage analysis identified tenascin-C (TNC) as a novel causative gene in nonsyndromic hearing loss. PLoS ONE. 2013;8:e69549.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Zhang L, Hu L, Chai Y, Pang X, Yang T, Wu H. A dominant mutation in the stereocilia-expressing gene TBC1D24 is a probable cause for nonsyndromic hearing impairment. Hum Mutat. 2014;35:814–8.

    CAS  PubMed  Google Scholar 

  123. 123.

    Xing G, Yao J, Wu B, Liu T, Wei Q, Liu C, et al. Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing. Genet Med. 2015;17:210–8.

    CAS  PubMed  Google Scholar 

  124. 124.

    Gao J, Wang Q, Dong C, Chen S, Qi Y, Liu Y. Whole Exome Sequencing Identified MCM2 as a Novel Causative Gene for Autosomal Dominant Nonsyndromic Deafness in a Chinese Family. PLoS ONE. 2015;10:e0133522.

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Gao X, Yuan Y-Y, Lin Q-F, Xu J-C, Wang W-Q, Qiao Y-H, et al. Mutation of, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss. J Med Genet. 2018;55:298–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Chen D-Y, Liu X-F, Lin X-J, Zhang D, Chai Y-C, Yu D-H, et al. A dominant variant in DMXL2 is linked to nonsyndromic hearing loss. Genet Med. 2017;19:553–8.

    CAS  PubMed  Google Scholar 

  127. 127.

    Wang L, Feng Y, Yan D, Qin L, Grati M’H, Mittal R, et al. A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss. Hum Genet. 2018;137:437–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Xia W, Hu J, Ma J, Huang J, Wang X, Jiang N, et al. Novel TRRAP mutation causes autosomal dominant non‐syndromic hearing loss. Clin Genet. 2019;96:300–8.

    CAS  PubMed  Google Scholar 

  129. 129.

    Lu X, Zhang Y, Chen L, Wang Q, Zeng Z, Dong C, et al. Whole exome sequencing identifies SCD5 as a novel causative gene for autosomal dominant nonsyndromic deafness. Eur J Med Genet. 2020;63:103855.

    PubMed  Google Scholar 

  130. 130.

    Li J, Zhao X, Xin Q, Shan S, Jiang B, Jin Y, et al. Whole-Exome Sequencing Identifies a Variant in Causing Autosomal-Recessive Nonsyndromic Hearing Loss DFNB99. Hum Mutat. 2015;36:98–105.

    PubMed  Google Scholar 

  131. 131.

    Zong L, Guan J, Ealy M, Zhang Q, Wang D, Wang H, et al. Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder. J Med Genet. 2015;52:523–31.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by National Natural Science Foundation of China (No. 81530029, 81720108010, 81800919, and 81971240) and by Shanghai Health System (No. 2017YQ010).

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Zhang, Z., Wang, J., Li, C. et al. Gene therapy development in hearing research in China. Gene Ther 27, 349–359 (2020). https://doi.org/10.1038/s41434-020-0177-1

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